We are going to discuss different aspects of dengue fever over the next couple weeks. This is the single most important arthropod-borne viral infection in the world, and may be second in importance only to malaria in terms of overall arthropod-borne infections. You may be thinking right now...what the heck is an arthropod, and what does this thing have to do with infections? Well, an arthropod is any organism that has an exoskeleton, a segmented body, and jointed legs. That means arthropods include many different organisms, such as insects, crabs, lobsters, spiders, and scorpions, just to name a very few. Of course, not all of these arthropods transmit dengue. When we talk about this particular arthropod-borne infection, the arthropods we are talking about specifically are the mosquitoes that act as vectors in transmitting dengue virus. In epidemiology, a vector is simply an animal (usually an arthropod) acting as a pathogen carrier that can transmit an infection from one host to another. So dengue virus has a mosquito vector, and it is called an arthropod-borne virus (or arbovirus) because the mosquito is an arthropod. There are other arthropod-borne infections, whose vectors are not mosquitoes, but are still arthropods. An example of this is Lyme disease, whose disease-causing organism (in this case a bacterium) is transmitted by a tick vector (ticks are not insects like the mosquito, but are still arthropods). We will cover Lyme disease in later weeks as we continue the series on arthropod-borne infections.
So...back to dengue fever. This week we are going to discuss the global burden of disease, and a little bit about the virus itself. Next week we will talk more about the landscape ecology of dengue as we explore the mosquitoes that transmit the virus, and the climate and habitats necessary for their survival. We will also talk about how the human impact on the environment affects human infection with dengue virus.
Dengue fever is typically a tropical and subtropical disease. The burden of this disease is largely concentrated along the lines of latitude of the Tropics of Cancer and Capricorn. If you look at this CDC map you can see that most cases of disease are concentrated equidistant from and along the equator between these two lines. Here is another representation published by the World Health Organization (WHO):
If you compare the above WHO map to the Centers for Disease Control and Prevention (CDC) map link above, you'll notice that while the risk of disease transmission extends along the equator between the tropical lines across the globe, the greatest number of cases of dengue fever are occurring in Latin America and South and Southeast Asia.
In order to describe the burden of disease accurately we need to describe the different forms this infection can take. The more common form is known as dengue fever and there are between 50 and 100 million cases per year across the globe. This disease is characterized by fever, headache, malaise, and often muscle and joint pain. Indeed, the joint pain can be so intense in some cases that the disease is also known as "break bone" fever because it can feel as though your bones are breaking. Another common symptom of dengue fever is a rash (maculopapular in type), which is typically localized. Minor bleeding (for example, the gums) may also sometimes occur in dengue fever, but pronounced bleeding is not common in this more minor form of infection.
Dengue fever is typically self-limiting and is not usually associated with severe complications. You may feel quite sick for awhile, but full recovery is the common course. In fact, many cases of this form of infection are completely asymptomatic. So someone can become infected with dengue virus and have no idea they are infected.
Dengue virus has another form, however, and this is far more devastating. Dengue hemorrhagic fever (DHF) is a much more serious disease and can kill. DHF is characterized by loss of fluid from the circulation and subsequent hemorrhage, often severe, and typically involves the eye, oral cavity, and the gastrointestinal tract, which can often demonstrate the most severe bleeding. The dysfunctional circulation and loss of fluid also leads to diminished blood supply to tissues (known as hypoperfusion) and can ultimately lead to organ failure and death. The case fatality for DHF is between 5% and 15%. This means that of every 100 people who acquire DHF, between 5 and 15 people will die from it. This is a very large number when you consider that approximately 250,000 people get DHF each year. What makes this disease so incredibly poignant is the rate at which it is growing each year. Take a look at this WHO graph to see the phenomenal rate of growth of dengue infection over the past 50 years:
But, you may be asking, if only a quarter of a million people acquire the severe hemorrhagic form of dengue, and if only 5% to 15% of these will die from the disease, even though any deaths are unacceptable from a public health perspective, how does this disease constitute a major global health threat (and I contend that it does) when compared to infections like HIV, malaria and tuberculosis, which together kill tens of millions of people each year, not just tens of thousands as dengue does? Well, the answer I would give is down to three major factors: 1) the nature of the virus, 2) the explosive growth of dengue infection across the world in recent decades as depicted in the graph above, and 3) the expansion of the vector mosquito that transmits dengue virus. The explosion in global infections in recent decades has much to do with mosquito abundance and habitat, which we are going to cover next time. But the nature of the virus itself is also extremely important in the consideration of dengue as a disease of major public health importance. So let's take a closer look at this virus now.
Just in case you were wondering, here is a representation of what the virus looks like:
This virus belongs to the family of viruses known as the Flaviviridae. Flaviviruses include many other arthropod-born viruses, including, for example, West Nile virus, Japanese encephalitis virus, St. Louis encephalitis virus, and yellow fever virus. All of these Flaviviruses are also transmitted by mosquitoes, although not all by the same mosquitoes, and not all Flaviviruses that exist are mosquito-borne or even vector-borne.
Critical to the epidemiology of dengue fever and dengue hemorrhagic fever, the dengue virus is comprised of 4 distinct serotypes. These are uncreatively known as dengue 1, dengue 2, dengue 3, and dengue 4. At least they are easy to remember! Dengue infection severity is believed to come down to infection with multiple serotypes. It is thought to go something like this: an individual is infected with any one of the 4 dengue serotypes circulating in his/her specific geographic region. The distribution of these serotypes is distinctly different across different geographical landscapes, but inevitably there are multiple serotypes in circulation wherever dengue is endemic. So an individual gets their first infection with one of the serotypes. They may or may not have symptoms with acute disease. If they do demonstrate clinical disease, they typically present with the dengue fever form of the disease, which was described above as demonstrating fever, headache, malaise, and perhaps a rash and severe joint and muscle pain. But the individual will most frequently recover completely and resume a healthy existence. Or, they may not have any symptoms whatsoever, and thus never know when they were first infected with the dengue virus. This is how it typically goes with your first dengue serotype infection. And indeed you will be immune to infection with this serotype upon any further contact with it.
However, the infection with the first serotype has done something a little bit nasty. It has sensitized you, in a particular way, to detrimental effects from new infections with dengue serotypes that are different from the serotype that originally infected you. Even though your immune system effectively controlled and cleared the first dengue infection, you have become immunologically primed to over-react to subsequent infections with different dengue serotypes. The causes behind this are believed to stem from the following mechanisms. To begin, there are receptors on the cells lining blood vessels, known as endothelial cells, that become hypersensitized to dengue virus-associated antibodies that were produced during your first dengue infection. These antibodies bind to the dengue virus antigen of different serotypes, creating immune complexes that likely trigger an inflammatory cascade that can cause vascular damage and "leaking" of the micro-vasculature (i.e. the very small blood vessels). This leads to the bleeding and reduced perfusion common in DHF and dengue shock syndrome (DSS). It is important to note that we are at an early stage in understanding the mechanics of this disease. For example, there may be certain serotypes that are associated with greater risk of DHF upon secondary infection. For instance, dengue 2 infection following dengue 1 infection may be more important for DHF than dengue 4 infection following dengue 1. In addition, there is much to the specific molecular mechanisms involved in DHF and DSS that is unknown, so the above description is only meant to be a rough thumbnail sketch of the basic process that is currently believed to be involved in the pathway from multiple dengue serotype infection to more severe dengue disease. This is currently an extremely active area of ongoing research and there is much that remains unknown.
Incidentally, this unique character of more severe disease associated with primary and secondary infection with different dengue serotypes is precisely why vaccine development has been difficult for dengue. Any vaccine must provide immunity on two fronts. First, it must be protective against all 4 serotypes of the virus. Second, it must provide long-lived immunity. Failure of any vaccine to do both would likely put the recipient at increased risk for the more severe dengue hemorrhagic fever because it may serve to prime the host immune system for hypersensitivity to future exposure to dengue virus in much the same way that natural infection with one serotype increases the risk for DHF after exposure to another serotype. This is not to say that a safe effective vaccine is not possible. It is challenging, but there are candidates under investigation.
So, let's return to the burden of disease and summarize what we know about dengue so far and why this constitutes an important global public health threat. Given that there is an annual incidence of dengue fever of 50 to 100 million persons per year, AND given the dramatic increase in the rate of infection that has been steadily increasing since the 1950s, AND given that the severe form of dengue disease is associated with secondary infection with a different dengue serotype following the recovery of the first, AND given that the landscape of this disease is such that those who were at risk for their first infection are equally at risk for their second, there are currently billions of people at risk for contracting dengue hemorrhagic fever. It is simply a matter of time before the lives claimed by DHF expand on a global scale exactly according to how the less severe form of infection has expanded.
That is, unless we do something to change the landscape of infection.
Next time we will discuss the vector of the dengue virus, the mosquito of the genus Aedes, and the two species that are responsible for transmission, A. aegypti, the more important vector, and A. albopictus, the lesser but still significant vector. We will place the vector squarely in the context of landscape epidemiology and describe how landscapes of both mosquito habitat and human habitation are central to the spread and control of dengue fever.
We will also end with a discussion on the emergence of dengue fever in the United States, which is now underway.